Candidate. The candidate, David L. Allen, Ph.D., is a research associate with extensive experience in both physiology and molecular biology. Dr. Allen's past and current research has focused on the cellular and molecular mechanisms underlying skeletal muscle adaptation in animals. His immediate career goal is to acquire any and all research and professional skills necessary for achieving his long-term goal of developing an independent, extramurally-funded translational research program focusing on the molecular mechanisms underlying exercise adaptation in both animals and humans. The proposed development plan will provide Dr. Allen with the additional experience and training necessary to achieve this goal. Career Development plan. Dr. Allen's proposed training activities consist of: (1) acquiring new research skills associated with the proposed research plan; (2) structured activities including attendance and presentation at journal clubs, colloquia, and national and local scientific meetings, and regular interactions with his mentoring team. Environment. The primary sponsor, Dr. Douglas Seals, is an extramurally funded scientist with a record of mentoring and two decades of experience in human exercise research; the co-sponsors provide guidance in specific components of the research plan, including muscle physiology, molecular biology, and genetics. Research. The hypotheses to be tested in this proposal are the following: (1) increased expression of matrix metalloproteinases (MMPs) is a central component of eccentric exercise-induced muscle damage and/or repair; (2) variations in transcription as a consequence of promoter polymorphisms in the MMP genes are responsible for at least part of the variation in muscle damage and soreness in humans following eccentric exercise. Systemic and muscle MMP levels will be assessed in human subjects following a bout of eccentric exercise and will be correlated with indices of muscle damage and muscle soreness. In addition, pharmacological and genetic manipulations will be used in mice to directly evaluate the causal role of MMPs in muscle damage and repair. Finally, subjects will be genotyped for known functional MMP promoter polymorphisms, which will be correlated with MMP levels and muscle damage and soreness following eccentric exercise.